tbuckley/cabot-search huggingface dataset:
A systematic review and evidence assessment of monogenic gene–disease relationships in human female infertility and differences in sex development
Authors: Annelore Van Der Kelen, Özlem Okutman, Elodie Javey, Münevver Serdarogullari, Charlotte Janssens, Manjusha S Ghosh, Bart J H Dequeker, Florence Perold, Claire Kastner, Emmanuelle Kieffer, Ingrid Segers, Alexander Gheldof, Frederik J Hes, Karen Sermon, Willem Verpoest, Stéphane Viville
Journal: Human Reproduction Update (2022)

Abstract BACKGROUND As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene–disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. OBJECTIVE AND RATIONALE An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. SEARCH METHODS PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. OUTCOMES A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. WIDER IMPLICATIONS We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.
Aging is associated with a systemic length-associated transcriptome imbalance
Authors: Thomas Stoeger, Rogan A Grant, Alexandra C McQuattie-Pimentel, Kishore R Anekalla, Sophia S Liu, Heliodoro Tejedor-Navarro, Benjamin D Singer, Hiam Abdala-Valencia, Michael Schwake, Marie-Pier Tetreault, Harris Perlman, William E Balch, Navdeep S Chandel, Karen M Ridge, Jacob I Sznajder, Richard I Morimoto, Alexander V Misharin, G R Scott Budinger, Luis A Nunes Amaral
Journal: Nature Aging (2022)

Abstract Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.
Targeting neuroinflammation in neuropathic pain and opioid use
Authors: Daniela Salvemini, Timothy M. Doyle
Journal: The Journal of Experimental Medicine (2022)

Neuropathic pain arises from injuries to the nervous system. It affects 20% of the adult US population and poses a major socioeconomic burden yet remains exceedingly difficult to treat. Current therapeutic approaches have limited efficacy and a large side effect profile that impedes their ability to treat neuropathic pain effectively. Preclinical research over the last 30 yr has established the critical role that pro-inflammatory neuro-immune cell interactions have in the development and maintenance of neuropathic pain arising from various etiologies. Pro-inflammatory neuro-immune cell interactions also underlie the development of adverse side effects of opioids and the loss of their efficacy to treat pain. Evidence from work in our lab and others in preclinical animal models have shown that signaling from the bioactive sphingolipid, sphingosine-1-phosphate (S1P), through the S1P receptor subtype 1 (S1PR1) modulates neuro-immune cell interactions. Here, we discuss how targeting S1P/S1PR1 signaling with S1PR1 antagonists already Food and Drug Administration-approved or in clinical trials for multiple sclerosis can provide a viable pharmacotherapeutic approach to reduce neuro-immune cell inflammatory signaling and potentially treat patients suffering neuropathic pain and the adverse effects of opioids.
Nucleophagy delays aging and preserves germline immortality
Authors: Margarita-Elena Papandreou, Georgios Konstantinidis, Nektarios Tavernarakis
Journal: Nature Aging (2022)

Marked alterations in nuclear ultrastructure are a universal hallmark of aging, progeroid syndromes and other age-related pathologies. Here we show that autophagy of nuclear proteins is an important determinant of fertility and aging. Impairment of nucleophagy diminishes stress resistance, germline immortality and longevity. We found that the nematode Caenorhabditis elegans nuclear envelope anchor protein, nuclear anchorage protein 1 (ANC-1) and its mammalian ortholog nesprin-2 are cleared out by autophagy and restrict nucleolar size, a biomarker of aging. We further uncovered a germline immortality assurance mechanism, which involves nucleolar degradation at the most proximal oocyte by ANC-1 and key autophagic components. Perturbation of this clearance pathway causes tumor-like structures in C. elegans, and genetic ablation of nesprin-2 causes ovarian carcinomas in mice. Thus, autophagic recycling of nuclear components is a conserved soma longevity and germline immortality mechanism that promotes youthfulness and delays aging under conditions of stress.
Neocortical synaptic engrams for remote contextual memories
Authors: Ji-Hye Lee, Woong Bin Kim, Eui Ho Park, Jun-Hyeong Cho
Journal: Nature Neuroscience (2022)

While initial encoding of contextual memories involves the strengthening of hippocampal circuits, these memories progressively mature to stabilized forms in neocortex and become less hippocampus dependent. Although it has been proposed that long-term storage of contextual memories may involve enduring synaptic changes in neocortical circuits, synaptic substrates of remote contextual memories have been elusive. Here we demonstrate that the consolidation of remote contextual fear memories in mice correlated with progressive strengthening of excitatory connections between prefrontal cortical (PFC) engram neurons active during learning and reactivated during remote memory recall, whereas the extinction of remote memories weakened those synapses. This synapse-specific plasticity was CREB-dependent and required sustained hippocampal signals, which the retrosplenial cortex could convey to PFC. Moreover, PFC engram neurons were strongly connected to other PFC neurons recruited during remote memory recall. Our study suggests that progressive and synapse-specific strengthening of PFC circuits can contribute to long-term storage of contextual memories.
The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer
Authors: Andrew Chow, Fathema Z. Uddin, Michael Liu, Anton Dobrin, Barzin Y. Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E. Tischfield, Alvaro Quintanal-Villalonga, Joseph M. Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene Kwong, Matthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S. Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L. Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A. Klebanoff, Matthew D. Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D. Wolchok, Taha Merghoub, Charles M. Rudin
Journal: Immunity (2022)
Computational Methods for Single-Cell Multi-Omics Integration and Alignment
Authors: Stefan Stanojevic, Yijun Li, Aleksandar Ristivojevic, Lana X. Garmire
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Recently developed technologies to generate single-cell genomic data have made a revolutionary impact in the field of biology. Multi-omics assays offer even greater opportunities to understand cellular states and biological processes. The problem of integrating different omics data with very different dimensionality and statistical properties remains, however, quite challenging. A growing body of computational tools is being developed for this task, leveraging ideas ranging from machine translation to the theory of networks, and represents another frontier on the interface of biology and data science. Our goal in this review is to provide a comprehensive, up-to-date survey of computational techniques for the integration of single-cell multi-omics data, while making the concepts behind each algorithm approachable to a non-expert audience.
Premotor, nonmotor and motor symptoms of Parkinson's Disease: A new clinical state of the art
Authors: Ana Beatriz Ramalho Leite Silva, Roger Wilson Gonçalves de Oliveira, Guilherme Pinheiro Diógenes, Marina Feitosa de Castro Aguiar, Camilla Costa Sallem, Micael Porto Portela Lima, Luciano Barroso de Albuquerque Filho, Sara Diógenes Peixoto de Medeiros, Lucas Lopes Penido de Mendonça, Paulo Cesar de Santiago Filho, Diogo Pasquali Nones, Pamella Mendes Martiniano da Silva Cardoso, Michelle Zonkowski Ribas, Stéfani Lara Galvão, Gabriel Felipe Gomes, Amanda Rebouças Bezerra de Menezes, Nayla Lima Dos Santos, Victor Monteiro Mororó, Fairane Sousa Duarte, Júlio César Claudino Dos Santos
Journal: Ageing Research Reviews (2022)
Multinational consensus antimicrobial stewardship recommendations for children managed in hospital settings
Authors: Brendan McMullan, Penelope A Bryant, Eamon Duffy, Julia Bielicki, Pieter De Cock, Michelle Science, Tracy Zembles, Kathryn Timberlake, Elizabeth Monsees, Rana F Hamdy, Alison C Tribble, Jason Newland, Sanjay Patel
Journal: The Lancet Infectious Diseases (2022)
Longitudinal Assessment of Labor Market Earnings Among Patients Diagnosed With Cancer in Canada
Authors: Young Jung, Christopher Longo, Emile Tompa
Journal: JAMA Network Open (2022)

Importance To our knowledge, there have been no studies that estimated the short-, mid-, and long-term effects on cancer survivors’ labor market earnings using administrative data. Objective To estimate the change in labor market earnings due to cancer diagnosis stratified by cancer type and age category. Design, Setting, and Participants This population-based cohort study used a retrospective analysis of Statistics Canada’s administrative linkage file, which includes microdata from the 1991 Census, the Canadian Cancer Registry, mortality records, and personal income tax files. Participants included patients newly diagnosed with cancer from 1992 to 2008. All statistical analyses were finished on September 30, 2020. Exposures Cancer diagnosis using the International Classification of Diseases, Ninth Revision , and the International Classification of Diseases, Tenth Revision. Main Outcomes and Measures Annual and percent change in labor market earnings. The empirical strategy used a combination of the Mahalanobis distance and propensity score matching method and the difference-in-difference regression method to select a control group similar to the cancer survivors in this study and assess the association of the cancer diagnosis with labor market earnings, respectively. Results A total of 59 532 patients with cancer and 243 446 patients without cancer were included in the main analysis. The mean (SD) age was similar between the matched treatment and control cohort (49.70 [8.1] years vs 49.68 [7.2] years), as was the proportion of females (0.49 vs 0.49), and the individual reported income ($37 937 [$18 645] vs $37 396 [$16 876]). The results showed the negative associations of cancer with labor market earnings. Additionally, the severity of the cancer was associated with labor market earnings, where cancer survivors with a severe type of cancer in terms of the 5-year survival rate are shown to have a larger and more persistent earnings difference compared with the control group. Conclusions and Relevance The findings of this cohort study suggest that labor market earnings losses are associated with a cancer diagnosis. A better understanding of the loss of labor market earnings following cancer diagnosis and by cancer type can play an important role in starting a dialogue in future policy initiatives to mitigate the financial burden faced by cancer survivors.
Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers
Authors: Katherine McDermott, Michael Fang, Andrew J.M. Boulton, Elizabeth Selvin, Caitlin W. Hicks
Journal: Diabetes Care (2022)

Diabetic foot ulcers (DFU) are a major source of preventable morbidity in adults with diabetes. Consequences of foot ulcers include decline in functional status, infection, hospitalization, lower-extremity amputation, and death. The lifetime risk of foot ulcer is 19% to 34%, and this number is rising with increased longevity and medical complexity of people with diabetes. Morbidity following incident ulceration is high, with recurrence rates of 65% at 3–5 years, lifetime lower-extremity amputation incidence of 20%, and 5-year mortality of 50–70%. New data suggest overall amputation incidence has increased by as much as 50% in some regions over the past several years after a long period of decline, especially in young and racial and ethnic minority populations. DFU are a common and highly morbid complication of diabetes. The pathway to ulceration, involving loss of sensation, ischemia, and minor trauma, is well established. Amputation and mortality after DFU represent late-stage complications and are strongly linked to poor diabetes management. Current efforts to improve care of patients with DFU have not resulted in consistently lower amputation rates, with evidence of widening disparities and implications for equity in diabetes care. Prevention and early detection of DFU through guideline-directed multidisciplinary care is critical to decrease the morbidity and disparities associated with DFU. This review describes the epidemiology, presentation, and sequelae of DFU, summarizes current evidence-based recommendations for screening and prevention, and highlights disparities in care and outcomes.
“The Times They Are A-Changin’” at <i>Diabetes Care</i>
Authors: Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse, Elizabeth Selvin, Sonia Y. Angell, Vanita R. Aroda, Jessica R. Castle, Alice Y.Y. Cheng, Thomas Danne, Justin B. Echouffo-Tcheugui, Jose C. Florez, Meghana D. Gadgil, Amalia Gastaldelli, Jennifer B. Green, Ania M. Jastreboff, Alka M. Kanaya, Namratha R. Kandula, Csaba P. Kovesdy, Neda Laiteerapong, Kristen J. Nadeau, Rodica Pop-Busui, Camille E. Powe, Casey M. Rebholz, Michael R. Rickels, Naveed Sattar, Jonathan E. Shaw, Emily K. Sims, Kristina M. Utzschneider, Adrian Vella, Cuilin Zhang
Journal: Diabetes Care (2022)
Response to Comment on Lachin et al. Association of Estimated Time-in-Range Capillary Glucose Levels Versus HbA1c With Progression of Microvascular Complications in the Diabetes Control and Complications Trial. Diabetes Care 2022;45:2445–2448
Authors: John M. Lachin, Ionut Bebu, Xiaoyu Gao, David M. Nathan, Bernard Zinman
Journal: Diabetes Care (2022)

We appreciate the opportunity to address the further comments from Drs. Ceriello and Prattichizzo (1) on our article (2).First, while further exploration of the relative contributions of the HbA 1c and time-in-range (TIR) would be of interest, as stated in the introduction of our article, our intention was to replicate the analyses of Beck et al. ( 3), which were built on data derived from the Diabetes Control and Complications Trial (DCCT).Thus, we only presented analyses of outcomes that had been included in the article by Beck et al.Second, we agree that the estimated TIR based on the seven-point profiles collected repeatedly during DCCT are an imperfect representation of TIR.However, continuous glucose monitoring was unavailable during DCCT and the seven-point profiles were the only method available to estimate TIR.These data were selected by Beck
Large-scale genomic and transcriptomic profiles of rice hybrids reveal a core mechanism underlying heterosis
Authors: Jianyin Xie, Weiping Wang, Tao Yang, Quan Zhang, Zhifang Zhang, Xiaoyang Zhu, Ni Li, Linran Zhi, Xiaoqian Ma, Shuyang Zhang, Yan Liu, Xueqiang Wang, Fengmei Li, Yan Zhao, Xuewei Jia, Jieyu Zhou, Ningjia Jiang, Gangling Li, Miaosong Liu, Shijin Liu, Lin Li, An Zeng, Mengke Du, Zhanying Zhang, Jinjie Li, Ziding Zhang, Zichao Li, Hongliang Zhang
Journal: Genome biology (2022)

Heterosis is widely used in agriculture. However, its molecular mechanisms are still unclear in plants. Here, we develop, sequence, and record the phenotypes of 418 hybrids from crosses between two testers and 265 rice varieties from a mini-core collection.
Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome
Authors: Anthony Scott, Felicia Hernandez, Adam Chamberlin, Cathy Smith, Rachid Karam, Jacob O. Kitzman
Journal: Genome biology (2022)

Abstract Background Lynch syndrome (LS) is a cancer predisposition syndrome affecting more than 1 in every 300 individuals worldwide. Clinical genetic testing for LS can be life-saving but is complicated by the heavy burden of variants of uncertain significance (VUS), especially missense changes. Result To address this challenge, we leverage a multiplexed analysis of variant effect (MAVE) map covering &gt;94% of the 17,746 possible missense variants in the key LS gene MSH2 . To establish this map’s utility in large-scale variant reclassification, we overlay it on clinical databases of &gt;15,000 individuals with LS gene variants uncovered during clinical genetic testing. We validate these functional measurements in a cohort of individuals with paired tumor-normal test results and find that MAVE-based function scores agree with the clinical interpretation for every one of the MSH2 missense variants with an available classification. We use these scores to attempt reclassification for 682 unique missense VUS, among which 34 scored as deleterious by our function map, in line with previously published rates for other cancer predisposition genes. Combining functional data and other evidence, ten missense VUS are reclassified as pathogenic/likely pathogenic, and another 497 could be moved to benign/likely benign. Finally, we apply these functional scores to paired tumor-normal genetic tests and identify a subset of patients with biallelic somatic loss of function, reflecting a sporadic Lynch-like Syndrome with distinct implications for treatment and relatives’ risk. Conclusion This study demonstrates how high-throughput functional assays can empower scalable VUS resolution and prospectively generate strong evidence for variant classification.
Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis
Authors: Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C. Are, Surinder K. Batra, Moorthy P. Ponnusamy
Journal: Molecular Cancer (2022)

Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer.
Extracellular vesicle microRNAs contribute to Notch signaling pathway in T-cell acute lymphoblastic leukemia
Authors: Tommaso Colangelo, Patrizio Panelli, Francesco Mazzarelli, Francesco Tamiro, Valentina Melocchi, Elisabetta De Santis, Roberto Cuttano, Orazio Palumbo, Giovanni Rossi, Fabrizio Bianchi, Vincenzo Giambra
Journal: Molecular Cancer (2022)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive T-cell malignancy characterized by genotypically-defined and phenotypically divergent cell populations, governed by adaptive landscapes. Clonal expansions are associated to genetic and epigenetic events, and modulation of external stimuli that affect the hierarchical structure of subclones and support the dynamics of leukemic subsets. Recently, small extracellular vesicles (sEV) such as exosomes were also shown to play a role in leukemia. Here, by coupling miRNome, bulk and single cell transcriptome profiling, we found that T-ALL-secreted sEV contain NOTCH1-dependent microRNAs (EV-miRs), which control oncogenic pathways acting as autocrine stimuli and ultimately promoting the expansion/survival of highly proliferative cell subsets of human T-cell leukemias. Of interest, we found that NOTCH1-dependent EV-miRs mostly comprised members of miR-17-92a cluster and paralogues, which rescued in vitro the proliferation of T-ALL cells blocked by γ-secretase inhibitors (GSI) an regulated a network of genes characterizing patients with relapsed/refractory early T-cell progenitor (ETP) ALLs. All these findings suggest that NOTCH1 dependent EV-miRs may sustain the growth/survival of immunophenotypically defined cell populations, altering the cell heterogeneity and the dynamics of T-cell leukemias in response to conventional therapies.